H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours

• DOI: 10.1038/s41467-024-48715-1
• Publication Date: 2024-05-24T15:01:45Z
• Authors: Diego Dibitetto; Martin Liptay; Francesca Vivalda; Hülya Dogan; Ewa Gogola; Martín González F...; Alexandra Duarte; Jonas A. Schmid; Morgane Decollogny; Paola Francica; Sara Przetocka; Stephen T. Durant; Josep V. Forment; Ismar Klebic; Myriam Siffert; Roebi de Bruijn; Arne N. Kousholt; Nicole A. Marti; Martina Dettwiler; Claus S. Sørensen; Jean-Christophe T...; Manuela Undurraga; Intidhar Labidi-Galy; Massimo Lopes; Alessandro A. Sar...; Jos Jonkers; Sven Rottenberg
• Keywords: BRCA2 Protein / genetics; Breast Neoplasms / drug therapy; DNA Repair; info:eu-repo/classification/ddc/616.07; BRCA2 Protein / deficiency; Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms / metabolism; BRCA2 Protein / metabolism; Histones; Mice; info:eu-repo/classification/ddc/616; info:eu-repo/classification/ddc/618; Ataxia Telangiectasia Mutated Proteins / metabolism; DNA Breaks, Double-Stranded; Tumor Suppressor p53-Binding Protein 1 / genetics; 630 Agriculture; BRCA1 Protein; 10061 Institute of Molecular Cancer Research; Q; Poly(ADP-ribose) Polymerase Inhibitors / pharmacology; Drug Resistance, Neoplasm / genetics; BRCA1 Protein / deficiency; 3100 General Physics and Astronomy; Rad51 Recombinase / genetics; Rad51 Recombinase / metabolism; Breast Neoplasms / pathology; Female; Tumor Suppressor p53-Binding Protein 1; Carrier Proteins / genetics; DNA Replication; BRCA1 Protein / genetics; Science; Mice, Nude; 1600 General Chemistry; 610 Medicine & health; Breast Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Article; 1300 General Biochemistry, Genetics and Molecular Biology; Cell Line, Tumor; Animals; Humans; Histones / metabolism; BRCA2 Protein; Carrier Proteins / metabolism; DNA Replication / drug effects; Ataxia Telangiectasia Mutated Proteins / genetics; Breast Neoplasms / genetics; Drug Resistance, Neoplasm; 570 Life sciences; biology; Tumor Suppressor p53-Binding Protein 1 / metabolism; Rad51 Recombinase; BRCA1 Protein / metabolism; Carrier Proteins; DNA Damage

Abstract Histone H2AX plays a key role in DNA damage signalling the surrounding regions of double-strand breaks (DSBs). In response to damage, becomes phosphorylated on serine residue 139 (known as γH2AX), resulting recruitment repair effectors 53BP1 and BRCA1. Here, by studying resistance poly(ADP-ribose) polymerase (PARP) inhibitors BRCA1/2-deficient mammary tumours, we identify function for γH2AX orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven degradation is elicited suppressing CtIP-mediated protection. As result, loss restores stability increases chemoresistance tumour cells without restoring homology-directed repair, highlighted lack damage-induced RAD51 foci. Furthermore, attempt discover acquired genetic vulnerabilities, find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) H2AX-deficient tumours interfering with summary, our results demonstrate biology BRCA-deficient establish separable from its classical DSB repair.